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Neurobiol Aging. 2015 Mar;36(3):1378-82. doi: 10.1016/j.neurobiolaging.2014.11.018. Epub 2014 Dec 3.

Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-β oligomer-treated hippocampal neurons.

Author information

1
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
2
Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
3
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada; Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. Electronic address: masilver@sfu.ca.

Abstract

Defective brain insulin signaling contributes to the cognitive deficits in Alzheimer's disease (AD). Amyloid-beta oligomers (AβOs), the primary neurotoxin implicated in AD, downregulate insulin signaling by impairing protein kinase B/AKT, thereby overactivating glycogen synthase kinase-3β. By this mechanism, AβOs may also impair axonal transport before tau-induced cytoskeletal collapse and cell death. Here, we demonstrate that a constitutively active form of protein kinase B/AKT prevents brain-derived neurotrophic factor (BDNF) transport defects in AβO-treated primary neurons from wild type (tau(+/+)) and tau knockout (tau(-/-)) mice. Remarkably, inhibition of glycogen synthase kinase-3β rescues BDNF transport defects independent of tau. Furthermore, exendin-4, an anti-diabetes agent, restores normal BDNF axonal transport by stimulating the glucagon-like peptide-1 receptor to activate the insulin pathway. Collectively, our findings indicate that normalized insulin signaling can both prevent and reverse BDNF transport defects in AβO-treated neurons. Ultimately, this work may reveal novel therapeutic targets that regulate BDNF trafficking, promote its secretion and uptake, and prolong neuronal survival during AD progression.

KEYWORDS:

Alzheimer's disease; Axonal transport; Brain-derived neurotrophic factor; GSK3beta; Hippocampal neuron; Insulin signaling

[Indexed for MEDLINE]

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